Primary hyperparathyroidism (PHPT), a disease of calcium metabolism, affects 1.5% of older Americans and may increase fracture risk. Limited data are available regarding the long-term effect of PHPT on bone mineral density (BMD). In collaboration with Kaiser Permanente Southern California, we have identified 3388 patients with PHPT using electronic laboratory screening. Most of these patients are elderly, and three-fourths have not been treated surgically. We have reported that elderly patients are unlikely to undergo surgery for PHPT, and furthermore, that surgery is frequently unsuccessful in the elderly. Hence it is critical to understand the natural history of this disease and the effect of medical therapies on skeletal health in order to optimize interventions aimed at reducing fracture risk in the elderly. We propose to examine long-term trends in BMD in this large cohort of patients with PHPT, while concurrently assessing the efficacy of medical therapies. We hypothesize that PHPT leads to accelerated bone loss if observed for =10 years without surgery, and that medical therapies and vitamin D adequacy mitigate adverse skeletal effects. The ethnically diverse population and the advanced informatics structure of Kaiser Permanente make this the only setting to our knowledge in which a study of this nature is feasible. This study has the following specific aims: 1. Assess changes in BMD at 5, 10, and >10 years in elderly patients with PHPT managed non-surgically. 2. Assess the effect of antiresorptive therapy, hormone replacement therapy, and vitamin D analogues on BMD in these patients. 3. Assess the relationship between serum vitamin D levels and BMD in these patients. The findings from this proposal will be used to: a. Create an inception cohort of elderly patients with PHPT and recorded BMD data that will be evaluated prospectively for further changes in BMD and fracture incidence (Immediate next step). b. Combine with existing data on renal and cardiovascular outcomes in patients with PHPT to enable comparative effectiveness research on existing medical and surgical therapies (Immediate next step). c. Develop health systems interventions, effected through the existing Kaiser Permanente electronic medical record, to decrease fracture risk in elderly patients with PHPT (Long-term goal). These studies will provide the first large-scale characterization of the natural history of PHPT as regards skeletal health in the elderly, by examining a cohort demographically and socioeconomically representative of the larger U.S. population. They will also fill a critical knowledge gap regarding the efficacy of medical therapies. Definitive findings provided the highly-powered analyses will guide future health care policy regarding best clinical practice in the management of PHPT. PUBLIC HEALTH RELEVANCE: An estimated 500,000 older Americans are living with primary hyperparathyroidism, which may increase their fracture risk by 30-80%. Our preliminary findings indicate that in many cases, the disease is not treated and possibly not even recognized. As the elderly enjoy longer life expectancies today, this proposal will assess the long-term effect of primary hyperparathyroidism on bone mineral density in this population.